title: Quantifying the fitness advantage of polymerase substitutions in Influenza A/H7N9 viruses during adaptation to humans.
abstract: Adaptation of zoonotic influenza viruses towards efficient human-to-human transmissibility is a substantial public health concern. The recently emerged A/H7N9 influenza viruses in China provide an opportunity for quantitative studies of host-adaptation, as human-adaptive substitutions in the PB2 gene of the virus have been found in all sequenced human strains, while these substitutions have not been detected in any non-human A/H7N9 sequences. Given the currently available information, this observation suggests that the human-adaptive PB2 substitution might confer a fitness advantage to the virus in these human hosts that allows it to rise to proportions detectable by consensus sequencing over the course of a single human infection. We use a mathematical model of within-host virus evolution to estimate the fitness advantage required for a substitution to reach predominance in a single infection as a function of the duration of infection and the fraction of mutant present in the virus population that initially infects a human. The modeling results provide an estimate of the lower bound for the fitness advantage of this adaptive substitution in the currently sequenced A/H7N9 viruses. This framework can be more generally used to quantitatively estimate fitness advantages of adaptive substitutions based on the within-host prevalence of mutations. Such estimates are critical for models of cross-species transmission and host-adaptation of influenza virus infections.
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Fonville
authors.forename: David F
authors.initials: DF
authors.lastname: Burke
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Lewis
authors.forename: Leah C
authors.initials: LC
authors.lastname: Katzelnick
authors.forename: Colin A
authors.initials: CA
authors.lastname: Russell
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D019143:Evolution, Molecular; D056084:Genetic Fitness / Q000235:genetics*; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000235:genetics*; D007251:Influenza, Human / Q000821:virology*; D008957:Models, Genetic; D011157:Population Dynamics; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase